tbuckley/cabot-search huggingface dataset:
Wnt signaling in colorectal cancer: pathogenic role and therapeutic target
Authors: Hui Zhao, Tianqi Ming, Shun Tang, Shan Ren, Han Yang, Maolun Liu, Qiu Tao, Haibo Xu
Journal: Molecular Cancer (2022)

Abstract Background The Wnt signaling pathway is a complex network of protein interactions that functions most commonly in embryonic development and cancer, but is also involved in normal physiological processes in adults. The canonical Wnt signaling pathway regulates cell pluripotency and determines the differentiation fate of cells during development. The canonical Wnt signaling pathway (also known as the Wnt/β-catenin signaling pathway) is a recognized driver of colon cancer and one of the most representative signaling pathways. As a functional effector molecule of Wnt signaling, the modification and degradation of β-catenin are key events in the Wnt signaling pathway and the development and progression of colon cancer. Therefore, the Wnt signaling pathway plays an important role in the pathogenesis of diseases, especially the pathogenesis of colorectal cancer (CRC). Objective Inhibit the Wnt signaling pathway to explore the therapeutic targets of colorectal cancer. Methods Based on studying the Wnt pathway, master the biochemical processes related to the Wnt pathway, and analyze the relevant targets when drugs or inhibitors act on the Wnt pathway, to clarify the medication ideas of drugs or inhibitors for the treatment of diseases, especially colorectal cancer. Results Wnt signaling pathways include: Wnt/β-catenin or canonical Wnt signaling pathway, planar cell polarity (Wnt-PCP) pathway and Wnt-Ca 2+ signaling pathway. The Wnt signaling pathway is closely related to cancer cell proliferation, stemness, apoptosis, autophagy, metabolism, inflammation and immunization, microenvironment, resistance, ion channel, heterogeneity, EMT/migration/invasion/metastasis. Drugs/phytochemicals and molecular preparations for the Wnt pathway of CRC treatment have now been developed. Wnt inhibitors are also commonly used clinically for the treatment of CRC. Conclusion The development of drugs/phytochemicals and molecular inhibitors targeting the Wnt pathway can effectively treat colorectal cancer clinically.
An unexpected finding during microscopy for urinary hemosiderin
Authors: Nehal Joshi, Ketan Patel, Maria Angeles, Daniel Pelling, Barbara J. Bain
Journal: American Journal of Hematology (2022)

A 59-year-old woman was admitted to intensive care after suffering a community cardiac arrest with ventricular fibrillation and 12 min downtime. She had a background of poorly controlled type 1 diabetes and severe chronic bilateral leg ulcers. A blood count showed hemoglobin concentration 85 g/L, mean cell volume 85.8 fL, red cell distribution width (RDW) 18.3% (normal range 10%–16%), and reticulocytes 117 × 109/L; the platelet count and total and differential white cell counts were normal. A blood film showed anisopoikilocytosis, with elliptocytes, polychromasia, vacuolation of neutrophils, and reactive lymphocytes. A direct antiglobulin test was positive (2+) for immunoglobulin G. Lactate dehydrogenase was mildly increased, but bilirubin was normal. C-reactive protein was greatly increased at 197 mg/L. Microbiological cultures from the ulcers identified Staphylococcus aureus and Citrobacter koseri. These organisms were thought to have caused overwhelming sepsis leading to cardiac arrest. A Perls stain for urinary hemosiderin was performed as part of investigation for suspected hemolysis. Unexpectedly, microscopy identified a partly filamentous microorganism with some budding yeast forms, which had been stained with the counterstain (images, ×100 objective). The presence of fungi was reported to clinical staff for further investigation and treatment. Laboratories performing microscopy on blood, bone marrow, or urine should be alert to unexpected findings that may alter clinical management. Often this is the unanticipated presence of a microorganism—a bacterium, a fungus, or a parasite. The authors declare no conflict of interest.
Four-Dimensional Computed Tomography of Paradoxical Motion of Eventrated Diaphragm Induced by Reverse Triggering
Authors: Ken Tonai, Shinshu Katayama, Kansuke Koyama, Shin Nunomiya
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Four-Dimensional Computed Tomography of Paradoxical Motion of Eventrated Diaphragm Induced by Reverse Triggering." American Journal of Respiratory and Critical Care Medicine, 206(6), pp. e70–e72
Response to the Article on Antibiotics and Immune Checkpoint Inhibitors by Lin et al.
Authors: Ka Shing Cheung, Wai K. Leung
Journal: Liver Cancer (2022)

We thank Lin KY et al for their comments on our manuscript entitled “Use of antibiotics during immune checkpoint inhibitors associates with lower survival in hepatocellular carcinoma”.1 Several issues were raised in the letter including the start time for survival analysis, the details of survival time with Kaplan-Meier curve and definition of cancer-related death. In the “Outcome definition” paragraph of our manuscript, it was mentioned that patients were observed from the start date of first immune checkpoint inhibitor as the index date till the occurrence of the outcome of interest or end of study. In the same paragraph, we have defined the primary outcome of cancer-related mortality as “liver cancer specified as the cause of death in the database” by the diagnosis codes. In the whole cohort, the 3-month, 6-month, 1-year and 2-year probability of cancer-related survival was 70.7% (95% CI: 66.3 – 75.4%), 57.4% (95% CI: 52.6 – 62.6%), 45.9% (95% CI: 41.1 – 51.4%) and 37.4% (32.4 – 43.3%), respectively. Figure 1 shows the Kaplan Meier survival plot of the whole cohort. Among the antibiotic users, the 3-month, 6-month, 1-year and 2-year probability of cancer-related survival was 50.9% (95% CI: 42.0 – 61.7%), 35.3% (95% CI: 26.9 – 46.4%), 26.8% (95% CI: 19.1 – 37.7%) and 19.3% (12.0 – 31.1%), respectively. For antibiotic non-users, the 3-month, 6-month, 1-year and 2-year probability of cancer-related survival was 77.8% (95% CI: 73.1 – 82.8%), 64.7% (95% CI: 59.4 – 70.6%), 52.2% (95% CI: 46.5 – 58.5%) and 43.6% (37.7– 50.5%), respectively. There was significant difference in cancer-related survival between the two groups (log-rank p &lt; 0.001). Figure 2 shows the Kaplan Meier survival plot according to antibiotic use.
Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma
Authors: Stephen M. Ansell, John Radford, Joseph M. Connors, Monika Długosz-Danecka, Won-Seog Kim, Andrea Gallamini, Radhakrishnan Ramchandren, Jonathan W. Friedberg, Ranjana Advani, Martin Hutchings, Andrew M. Evens, Piotr Smolewski, Kerry J. Savage, Nancy L. Bartlett, Hyeon-Seok Eom, Jeremy S. Abramson, Cassie Dong, Frank Campana, Keenan Fenton, Markus Puhlmann, David J. Straus
Journal: New England Journal of Medicine (2022)

Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody–drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.
A Better Treatment for Advanced-Stage Hodgkin’s Lymphoma?
Authors: Dan L. Longo, James O. Armitage
Journal: New England Journal of Medicine (2022)

Treatment for patients with Hodgkin's lymphoma is one of the success stories of modern medicine. A once uniformly fatal disorder is now curable, even in an advanced stage, in the great majority of patients. In fact, particularly in limited-stage Hodgkin's lymphoma, much of the therapeutic focus is on maintaining the high probability of cure while reducing the incidence of toxic effects. How little therapy can we give without losing efficacy? For patients with advanced-stage, high-risk disease, debates regarding the best currently available approach have centered on the "old standard" ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen,1 the very intensive escalated . . .
Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures
Authors: Roman A. Lukaszewski, Helen E. Jones, Vivian H. Gersuk, Paul Russell, Andrew Simpson, David Brealey, Jonathan Walker, Matt Thomas, Tony Whitehouse, Marlies Ostermann, Alexander Koch, Kai Zacharowski, Mogens Kruhoffer, Damien Chaussabel, Mervyn Singer
Journal: Intensive Care Medicine (2022)
Myocarditis and pericarditis risk after covid-19 vaccination
Authors: Jing Luo, Walid F Gellad
Journal: BMJ (2022)

<b>Objectives:</b> Many survivors of cardiac arrest are left with considerable long-term impairments due to a transient ischemic state of the brain. Neuropsychologists identified a wide range of neuropsychological deficits in these patients besides the well-known amnesic syndrome. To date, there is no complete and unbiased documentation of the affected brain areas in vivo. We aimed to identify the brain tissue atrophy underlying the observed neuropsychological deficits in a case-control study. <b>Methods:</b> We measured gray matter loss by voxel-based morphometry of 3-T structural magnetic resonance images in a sample of 12 patients who had had cardiac arrest with successful subsequent resuscitation in comparison with 12 individually age- and sex-matched control subjects. Such data are rare because many of these patients wear cardiac pacemakers. <b>Results:</b> We found extensive reductions of gray matter volumes in the anterior, medial, and posterior cingulate cortex, the precuneus, the insular cortex, the posterior hippocampus, and the dorsomedial thalamus in tight correlation with neuropsychological impairments, namely, amnestic deficits and apathy. <b>Conclusion:</b> The identified neuroanatomical pattern of brain tissue loss substantiates the reports of wide-ranging neuropsychological impairments in patients after cardiac arrest.
Atezolizumab plus Bevacizumab versus Sorafenib for Unresectable Hepatocellular Carcinoma: Results from Older Adults Enrolled in the IMbrave150 Randomized Clinical Trial
Authors: Daneng Li, Han Chong Toh, Philippe Merle, Kaoru Tsuchiya, Sairy Hernandez, Wendy Verret, Alan Nicholas, Masatoshi Kudo
Journal: Liver Cancer (2022)

The efficacy of systemic first-line treatments in older adults with unresectable hepatocellular carcinoma (HCC) has not been well-studied. We compared the safety and efficacy of atezolizumab plus bevacizumab versus sorafenib as a first-line treatment in younger versus older patients with unresectable HCC.This global, phase 3, open-label, randomized clinical trial (IMbrave150) recruited patients aged ≥18 years with locally advanced metastatic or unresectable HCC, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and Child-Pugh class A liver function who had not previously received systemic therapy for liver cancer. Patients received either 1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily until loss of clinical benefit or unacceptable toxicity. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the incidence of adverse events and time to deterioration of patient-reported outcomes (PROs). This subgroup analysis evaluated safety and efficacy endpoints in patients <65 years, ≥65 to <75 years, and ≥75 years.Of 501 patients, 165 patients were randomized to sorafenib and 336 were randomized to atezolizumab plus bevacizumab (175 patients <65 years; 106 patients ≥65 to <75 years; 55 patients ≥75 years). Across all age groups, patients receiving atezolizumab plus bevacizumab had longer median OS (<65: 18.0 vs. 12.2 months [HR, 0.57; 95% CI: 0.40-0.82]; ≥65 to <75: 19.4 vs. 14.9 months [HR, 0.80; 95% CI: 0.52-1.23]; ≥75: 24.0 vs. 18.0 months [HR, 0.72, 95% CI: 0.37-1.41]) and PFS than those receiving sorafenib. Time to deterioration for multiple PROs was delayed for patients receiving atezolizumab plus bevacizumab, including older adults. There were no clinically meaningful differences in toxicity between age groups.Atezolizumab plus bevacizumab is safe and effective in adults <65, ≥65 to <75, and ≥75. Treatment was well-tolerated even in elderly patients.
Safety and Efficacy of Bimekizumab in Patients With Active Ankylosing Spondylitis: <scp>Three‐Year</scp> Results From a Phase <scp>IIb</scp> Randomized Controlled Trial and Its <scp>Open‐Label</scp> Extension Study
Authors: Xenofon Baraliakos, Atul Deodhar, Maxime Dougados, Lianne S. Gensler, Anna Molto, Sofia Ramiro, Alan J. Kivitz, Denis Poddubnyy, Marga Oortgiesen, Thomas Vaux, Carmen Fleurinck, Julie Shepherd‐Smith, Christine de la Loge, Natasha de Peyrecave, Désirée van der Heijde
Journal: Arthritis & Rheumatology (2022)

To assess the long-term safety, tolerability, and efficacy of bimekizumab in patients with active ankylosing spondylitis (AS).Patients with active AS who completed the dose-ranging, 48-week BE AGILE randomized controlled trial were eligible to participate in an open-label extension (OLE) study, in which patients received 160 mg of bimekizumab every 4 weeks. We present the safety and efficacy results through 156 weeks. Missing efficacy data were imputed using nonresponder imputation analysis for binary outcomes and multiple imputation for continuous outcomes.From weeks 0-156, 280 of 303 patients (exposure-adjusted incidence rate 141.0 per 100 patient-years) experienced ≥1 treatment-emergent adverse event; the most frequent adverse events were nasopharyngitis (8.1 per 100 patient-years) and upper respiratory tract infection (5.0 per 100 patient-years). Additionally, 67 of 303 patients (9.8 per 100 patient-years) had mild to moderate localized fungal infections (28 of 303 patients had Candida infections [3.7 per 100 patient-years] and 23 of 303 patients had oral candidiasis [3.0 per 100 patient-years]), 10 patients had serious infections (1.3 per 100 patient-years), and no cases of active tuberculosis were reported. Active inflammatory bowel disease (1.1 per 100 patient-years), anterior uveitis (0.7 per 100 patient-years), and adjudicated major adverse cardiovascular events (0.3 per 100 patient-years) were infrequent. The efficacy of bimekizumab treatment demonstrated at week 48 was sustained in the OLE study. At week 156, nonresponder imputation analysis showed that 53.7% of patients (72.6% of observed cases) met the Assessment of SpondyloArthritis international Society criteria for 40% improvement and 28.0% of patients (37.9% of observed cases) achieved partial remission; Ankylosing Spondylitis Disease Activity Scores were reduced from baseline (mean ± SEM 3.9 ± 0.1) to week 48 (2.1 ± 0.1) and week 156 (1.9 ± 0.1) (multiple imputation). Patients showed sustained improvements in pain, fatigue, physical function, and health-related quality of life.The safety profile of bimekizumab was found to be consistent with previously demonstrated findings, and no new safety signals were identified. The efficacy of bimekizumab in patients with AS was sustained through 3 years of treatment.
A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection
Authors: L. Helena Gutierrez Sanchez, Henry Shiau, Julia M. Baker, Stephanie Saaybi, Markus Buchfellner, William Britt, Veronica Sanchez, Jennifer L. Potter, L. Amanda Ingram, David Kelly, Xiaoyan Lu, Stephanie Ayers-Millsap, Wesley G. Willeford, Negar Rassaei, Julu Bhatnagar, Hannah Bullock, Sarah Reagan-Steiner, Ali Martin, Michael E. Rogers, Anna M. Banc-Husu, Sanjiv Harpavat, Daniel H. Leung, Elizabeth A. Moulton, Daryl M. Lamson, Kirsten St. George, Aron J. Hall, Umesh Parashar, Adam MacNeil, Jacqueline E. Tate, Hannah L. Kirking
Journal: New England Journal of Medicine (2022)

Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia.
Correction: Refining colorectal cancer classification and clinical stratification through a single-cell atlas
Authors: Ateeq M. Khaliq, Cihat Erdogan, Zeyneb Kurt, Sultan Sevgi Turgut, Miles W. Grunvald, Tim Rand, Sonal Khare, Jefrey A. Borgia, Dana M. Hayden, Sam G. Pappas, Henry R. Govekar, Audrey E. Kam, Jochen Reiser, Kiran Turaga, Milan Radovich, Yong Zang, Yingjie Qiu, Yunlong Liu, Melissa L. Fishel, Anita Turk, Vineet Gupta, Ram Al-Sabti, Janakiraman Subramanian, Timothy M. Kuzel, Anguraj Sadanandam, Levi Waldron, Arif Hussain, Mohammad Saleem, Bassel El-Rayes, Ameen A. Salahudeen, Ashiq Masood
Journal: Genome biology (2022)
Isotretinoin: reasserting its public health value at the population level, addressing potential neuropsychiatric risk at the individual level
Authors: Olivier Chosidow, Marie Beylot-Barry, Florence Corgibet, Nicole Jouan, Nicolas Dupin, Bernard Guillot
Journal: British Journal of Dermatology (2022)

Abstract Linked Articles: Paljarvi et al. Br J Dermatol 2022; 187:64–72; Ravencroft and Eichenfield. Br J Dermatol 2022; 187:8–9.
Acute Hepatitis in Children in 2022 — Human Adenovirus 41?
Authors: Saul J. Karpen
Journal: New England Journal of Medicine (2022)

Acute hepatitis in children is certainly not new, and it can be worrisome. Successful worldwide vaccination campaigns over the past few decades have led to demonstrable improvements in public health and well-being by reducing the incidence and consequences of two viral causes — hepatitis A and B viruses. Many other viruses, some quite commonly encountered during childhood, are hepatotropic and in a minority of patients may cause illness that can escalate in severity. In these cases, liver damage manifests as elevations in serum levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), that can increase rapidly . . .
Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models
Authors: Filippo Birocchi, Melania Cusimano, Federico Rossari, Stefano Beretta, Paola M. V. Rancoita, Anna Ranghetti, Stefano Colombo, Barbara Costa, Peter Angel, Francesca Sanvito, Marcella Callea, Rossana Norata, Linda Chaabane, Tamara Canu, Antonello Spinelli, Marco Genua, Renato Ostuni, Ivan Merelli, Nadia Coltella, Luigi Naldini
Journal: Science Translational Medicine (2022)

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor characterized by a strongly immunosuppressive tumor microenvironment (TME) that represents a barrier also for the development of effective immunotherapies. The possibility to revert this hostile TME by immunoactivating cytokines is hampered by the severe toxicity associated with their systemic administration. Here, we exploited a lentiviral vector–based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, interferon-α (IFN-α) or interleukin-12 (IL-12) at the tumor site with spatial and temporal selectivity. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-α within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability, and specificity. Single-cell RNA sequencing of the tumor immune infiltrate revealed reprogramming of the immune microenvironment toward a proinflammatory and antitumoral state associated with loss of a macrophage subpopulation shown to be associated with poor prognosis in human GBM. The spatial and temporal control of IL-12 release was critical to overcome an otherwise lethal hematopoietic toxicity while allowing to fully exploit its antitumor activity. Overall, our findings demonstrate a potential therapeutic approach for GBM and set the bases for a recently launched first-in-human clinical trial in patients with GBM.
Online NHS 111 service made no difference to call handlers’ workload, study finds
Authors: Adrian O’Dowd
Journal: BMJ (2022)

<h3>Objectives</h3> To validate and assess reliability of a novel triage system, one-two-triage (OTT), that can be applied by inexperienced providers in low-resource settings. <h3>Methods</h3> This study was a two-phase prospective, comparative study conducted at three hospitals. Phase I assessed criterion validity of OTT on all patients arriving at an American university hospital by comparing agreement among three methods of triage: OTT, Emergency Severity Index (ESI) and physician-defined acuity (the gold standard). Agreement was reported in normalised and raw-weighted Cohen κ using two different scales for weighting, Expert-weighted and triage-weighted κ. Phase II tested reliability, reported in Fleiss κ, of OTT using standardised cases among three groups of providers at an urban and rural Cambodian hospital and the American university hospital. <h3>Results</h3> Normalised for prevalence of patients in each category, OTT and ESI performed similarly well for expert-weighted κ (OTT κ=0.58, 95% CI 0.52 to 0.65; ESI κ=0.47, 95% CI 0.40 to 0.53) and triage-weighted κ (κ=0.54, 95% CI 0.48 to 0.61; ESI κ=0.57, 95% CI 0.51 to 0.64). Without normalising, agreement with gold standard was less for both systems but performance of OTT and ESI remained similar, expert-weighted (OTT κ=0.57, 95% CI 0.52 to 0.62; ESI κ=0.6, 95% CI 0.58 to 0.66) and triage-weighted (OTT κ=0.31, 95% CI 0.25 to 0.38; ESI κ=0.41, 95% CI 0.35 to 0.4). In the reliability phase, all triagers showed fair inter-rater agreement, Fleiss κ (κ=0.308). <h3>Conclusions</h3> OTT can be reliably applied and performs as well as ESI compared with gold standard, but requires fewer resources and less experience.
Update to living systematic review on drug treatments for covid-19
Journal: BMJ (2022)

Update to living systematic review on drug treatments for covid-19This living systematic review by Siemieniuk and colleagues (BMJ 2020;370:m2980) has been updated.For the latest update, visit doi:.In this update, 463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration.Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids, interleukin-6 receptor antagonists when given with corticosteroids, and Janus kinase inhibitors.Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir and molnupiravir.Remdesivir may reduce hospital admission.Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution; several others showed a possible benefit.Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty).
Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause
Authors: Chayarani Kelgeri, Michael Couper, Girish L. Gupte, Alexandra Brant, Mitul Patel, Lauren Johansen, Joseph Valamparampil, Evelyn Ong, Hermien Hartog, M.T.P.R. Perera, Darius Mirza, Indra van Mourik, Khalid Sharif, Jane Hartley
Journal: New England Journal of Medicine (2022)

Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents.